1. Field of the Invention
The invention relates to a process for preparing an alpha-lipoic acid/cyclodextrin complex and product prepared.
2. Background Art
Cyclodextrins are cyclic oligosaccharides composed of 6, 7 or 8 α(1-4)-linked anhydroglucose units. The α-, β- or γ-cyclodextrins, which are prepared for example by enzymatic conversion of starch, differ in the diameter of their hydrophobic cavity and are generally suitable for inclusion of numerous lipophilic substances.
Alpha-lipoic acid (Thioctic Acid) is a naturally occurring molecule produced by both plants and animals. It serves as a cofactor for some enzymes and as an excellent antioxidant/free radical scavenger. Since it has been known that alpha-Lipoic Acid can improve insulin sensitivity in cases of Type II diabetes, alpha-Lipoic Acid has been employed for treating diabetes as well as alcoholic liver disease and other neuropathies.
Alpha-lipoic acid is a lipid-soluble substance. It is a yellowish powder and is unstable in light. Its solubility in water is very poor. A formulation with cyclodextrins, especially with alpha cyclodextrin, is stable to temperature and light and increases the dispersibility in water and the bioavailability. The complexes also reduce the unpleasant odour of alpha-lipoic acid.
The complexation of lipoic acid with α-cyclodextrin and β-cyclodextrin using a solution method is described in the Journal of Inclusion Phenomena and Molecular Recognition in Chemistry, (1995), vol. 23, pp. 119-96. The processes described therein for preparing a cyclodextrin complex with alpha-lipoic acid show various disadvantages in the laboratory and production scale. On use of the solution method on the production scale, the amount of water needed to solubilize the cyclodextrin is enormous. For economic reasons, therefore, these methods cannot be used commercially to prepare a cyclodextrin/alpha-lipoic acid complex. According to this literature the thermal stability of alpha-lipoic acid can be improved significantly by its inclusion in beta cyclodextrin. Calculation of the stability constants for the alpha-lipoic acid/cyclodextrin complex according to the Benesi-Hildebrand procedure are described also on page 121 of this paper. The calculated stability constants for the cyclodextrin complex with alpha cyclodextrin were 3.34 and for the beta cyclodextrin complex 3.95. According to these findings the beta cyclodextrin complex is more stable than the alpha cyclodextrin alpha-lipoic acid complex.
In Canadian patent application 2,135,535 a process is described characterized in that thioctic acid is suspended in water, cyclodextrins are added at elevated temperature such as 50° C., stirred for several hours, cooled down and the inclusion compound is isolated by filtration and vacuum dried. Working in suspension to produce cyclodextrins complexes requires elevated temperatures and long complexation times for efficient results. Elevated temperatures can have a negative impact on the stability of the alpha-lipoic acid.